Is ACTN2 p.Ile234= (c.702C>T) pathogenic?

ACTN2 p.Ile234= (c.702C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-15). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Ile234= (c.702C>T)?

ACTN2 p.Ile234= (c.702C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ile234= (c.702C>T) in the general population?

ACTN2 p.Ile234= (c.702C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

ACTN2 p.Ile234=

c.702C>T · rs751046389 · VCV2152699

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP -1.1, phastCons 1
Overall
CADD	11.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000424%	235,987

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACTN2
Protein: p.Ile234=
Coding: c.702C>T
MANE Select: NM_001103
dbSNP: rs751046389
Type: single nucleotide variant
Location: chr1:236735639 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 234: the calponin-homology (ch) 2 domain; an α-helix; the 'actin-binding' region

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Ile234Leu Uncertain significance ★★ ⚠ same residue
ACTN2 p.Ile234Asn Uncertain significance ★ ⚠ same residue
ACTN2 p.Ile234Val Uncertain significance ★ ⚠ same residue
ACTN2 p.Ile234Phe Uncertain significance ★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Thr247Met Likely pathogenic ★★ same condition
ACTN2 c.1107+3G>A Uncertain significance ★★ same condition
ACTN2 c.1108-10A>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/actn2-p-ile234 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown